Abstract
Rationale
Alterations in the central cholinergic system of patients with schizophrenia such as reduced numbers of muscarinic and nicotinic receptors in the cortex and hippocampus may contribute to the cognitive impairment of schizophrenia. Therefore, pharmacological treatments that enhance central cholinergic function may be useful as cognitive enhancers in schizophrenia.
Methods
Searches were conducted for articles which investigated alterations of central cholinergic systems in patients with schizophrenia. Additional searches were conducted for animal and human trials of potential cognitive enhancing compounds that target the cholinergic system and any preliminary trials conducted with schizophrenic patients.
Results
Currently available treatments which are potentially suitable for this purpose include acetylcholinesterase inhibitors, muscarinic agonists, nicotinic agonists, and allosteric potentiators of nicotinic receptor function. Although some open label studies demonstrate modest cognitive improvements of schizophrenic patients treated with donepezil, data from a blinded, placebo controlled study demonstrate no effect. Data from a controlled trial of galantamine, a combined acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic receptor, indicates that this may be an effective alternative. In addition, some preclinical data indicates that selective M1 muscarinic agonists under development may have potential as cognitive enhancers and antipsychotic treatments for schizophrenic patients.
Conclusions
A cholinergic approach to ameliorating the cognitive dysfunction of schizophrenia appears viable. There is some preliminary data to support the efficacy of combined acetylcholinesterase inhibitors and allosteric potentiators of the nicotinic receptor, whereas future trials are awaited for more specific muscarinic agonists currently under development.
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References
Adler LE, Hoffer LD, Wiser A, Freedman R (1993) Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 150:1856–1861
Aggleton J, Keith A, Rawlins J, Hunt P, Sahgal A (1992) Removal of the hippocampus and transection of the fornix produce comparable deficits on delyed non-match to position by rats. Behav Brain Res 52:61–71
Aigner T, Mishkin M (1986) The effects of physostigmine and scopolamine on recognition memory in monkeys. Behav Neural Biol 45:81–87
Allen T, McEvoy JP, Keefe R, Levin E, Wilson W (2003) Galantamine as an adjunctive therapy in the treatment of schizophrenia. Presented at 11th Congress of the International Psychogeriatric Association (IPA), Chicago, Ill., August 17–22
Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP, Nathanson NM, Silva AJ (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci 6:51–58
Andersen MB, Fink-Jensen A, Peacock L, Gerlach J, Bymaster F, Lundbaek JA, Werge T (2003) The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys. Neuropsychopharmacology 28:1168–1175
Arendash GW, Sengstock GJ, Sanberg PR, Kem WR (1995) Improved learning and memory in aged rats with chronic administration of the nicotinic receptor agonist GTS-21. Brain Res 674:252–259
Bartus R, Uehara Y (1979) Physostigmine and recent memory: effects in young and aged nonhuman primates. Science 206:1085–1087
Benwell ME, Balfour DJ, Birrell CE (1995) Desensitization of the nicotine-induced mesolimbic dopamine responses during constant infusion with nicotine. Br J Pharmacol 114:454–460
Blozovski D, Cudennec A, Garrigou D (1977) Deficits in passive avoidance learning following atropine in the developing rat. Psychopharmacology 54:139–144
Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM (1997) Effects of xanomaline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 54:465–473
Bolden C, Cusack B, Richelson E. (1992) Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther 260:576–580
Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S (2000) Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia. Neuropsychopharmacology 23:351–364
Briggs CA, Anderson DJ, Brioni JD, Buccafusco JJ, Buckley MJ, Campbell JE, Decker MW, Donnelly-Roberts D, Elliott RL, Gopalakrishnan M, Holladay MW, Hui YH, Jackson WJ, Kim DJ, Marsh KC, O’Neill A, Prendergast MA, Ryther KB, Sullivan JP, Arneric SP (1997) Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav 57:231–241
Brito G, Davis B, Stopp L, Stanton M (1983) Memory and the septohippocampal cholinergic system in the rat. Psychopharmacology 81:315–320
Buchanan RW, Summerfelt A, Tek C, Gold J (2003) An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia. Schizophr Res 59:29–33
Bymaster FP, Wong DT, Mitch CH, Ward JS, Calligaro DO, Schoepp DD, Shannon HE, Sheardown MJ, Olesen PH, Suzdak PD, et al. (1994). Neurochemical effects of the MI muscarinic agonist xanomeline. J Pharmacol Exp Ther 269:282–289
Callahan M, Kinsora J, Harbaugh R, Reeder T, Davis R (1993) Continuous icv infusion of scopolamine impairs sustained attention of rhesus monkeys. Neurobiol Aging 14:147–151
Caulfield MP, Muscarinic receptors—characterization, coupling and function (1993) Pharmacol Ther 58:319–379
Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B (2000) Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biol Psychiatry 48:381–388
Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B (2001) Low muscarinic receptor binding in prefrontal cortex from subjects with schizophrenia: a study of Brodmann’s areas 8, 9, 10, and 46 and the effects of neuroleptic drug treatment. Am J Psychiatry 158:918–925
Davidson M, Harvey PD, Welsh KA, Powchik P, Putnam KM<Mohs RC (1996) Cognitive functioning in late-life schizophrenia: A comparison of elderly schizophrenic patients with Alzheimer’s disease. Am J Psychiatry 153:1274–1279
Davis KL, Mohs R, Tinklenberg J, Pfefferbaum A, Hollister L, Kopell B (1978) Physostigmine: improvement of long-term memory in normal humans. Science 201:272–274
Dean B, Crook JM, Opeskin K, Hill C, Keks N, Copolov DL (1996) The density of muscarinic M1 receptors is decreased in the caudate-putamen of subjects with schizophrenia. Mol Psychiatry 1:54–58
Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E (2002) Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 7:1083–1091
Dunnett S (1985) Comparative effects of cholinergic drugs and lesions of the nucleus basalis or fimbria-fornix on delayed-matching in rats. Psychopharmacology 87:357–363
Eichenbaum H, Otto T, Cohen N (1994) Two functional components of the hippocampal memory system. Behav Brain Sci 17:449–518
El-Mallack R, Kirch D, Shelton R, Fan K, Pezeshkpour G, Kanhouwa S et al. (1991) The nucleus basalis of Meynert, senile plaques, and intellectual impairment in schizophrenia. J Neuropsychiatr Clin Neurosci 3:383–386
Fadda F, Melis F, Stancampiano R (1996) Increased hippocampal acetylcholine release during a working memory task. Eur J Pharmacol 307:R1–R2
Fenster CP, Whitworth TL, Sheffield EB, Quick MW, Lester RA (1999) Upregulation of Surgace alpha4beta2 nicotine receptors in initiated by receptor desensitization after chronic exposure to nicotine. J Neurosci 19:4804–4818
Flynn DD, Ferrari-DiLeo G, Mash DC, Levey AI (1995) Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer’s disease. J Neurochem 64:1888–1891
Frazier CJ, Rollins YD, Breese CR, Leonard S, Freedman R, Dunwiddie TV (1998) Acetylcholine activates an α-bungarotoxin-sensitive nicotinic current in rat hippocampal interneurons, but not pyramidal cells. J Neurosci 18:1187–1195
Freedman R, Hall M, Adler LE, Leonard S (1995) Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol Psychiatry 38:22–33
Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci 94:587–592
Friedman JI, Adler DN, Howanitz E, Harvey PD, Brenner G, Temporini H, White L, Parrella M, Davis KL (2002) A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biol Psychiatry 51:349–357
Gerber DJ, Sotnikova TD, Gainetdinov RR, Huang SY, Caron MG, Tonegawa S (2001) Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice. Proc Natl Acad Sci USA 98:15312–15317
Goldberg T, Weinberger D, Pliskin N, berman K, Podd M (1989) Recall memory deficit in schizophrenia: a possible manifestation of prefrontal dysfunction. Schizophr Res 2:251–257
Hagan JJ, Jansen JH, Broekkamp CL (1987) Blockade of spatial learning by the M1 muscarinic antagonist pirenzepine. Psychopharmacology 93:470–476
Harvey PD, Keefe RS (2001) Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry 158:176–184
Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA (1986) Prevalence of smoking among psychiatric outpatients. Am J Psychiatry 143:993–997
Ichikawa J, Dai J, O’Laughlin A, Fowler WL, Meltzer HY (2002) Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum. Neuropsychopharmacology 26:325–339
Iga Y, Arisawa H, Ogane N, Saito Y, Tomizuka T, Nakagawa-Yagi Y, Masunaga H, Yasuda H, Miyata N (1998) (±)-cis-2-methylspiro[1,3-oxathiolane-5,3’-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride) induces saliva and tear secretions in rats and mice: the role of muscarinic acetylcholine receptors. Jpn J Pharmacol 78:373–380
Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI (1994) A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The Tacrine Study Group. JAMA 271:985–991
Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR (1991) Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci 11:3218–3226
Luntz-Leybman V, Bickford PC, Freedman R (1992) Cholinergic gating of response to auditory stimuli in rat hippocampus. Brain Res 587:130–136
Maelicke A, Albuquerque EX (1996) New approach to drug therapy in Alzheimer’s disease. Drug Discovery Today 1:53–59
Maelicke A, Schrattenholz A, Storch A, Schroder B, Gutrod O, Methfessel C, Weber KH, Pereira EE, Alkondon M, Albuquerque EX (1995) Noncompetitive agonism at nicotinic acetylcholine receptors; functional significance for CNS signal transduction. J Recept Signal Transduct Res 15:333–353
Mandel R, Chen A, Connor D, Thal L (1989) Continuous physostigmine infusion in rats with excitotoxic lesions of the nucleus basalis magnocellularis: effects on performance in the water maze task and cortical cholinergic markers. J Pharmacol Exp Ther 251:612–619
McAlonan G, Wilkinson L, Robbins T, Everitt B (1995) The effects of AMPA-induced lesions of the septohippocampal cholinergic projection on aversive conditioning to explicit and contextual cues and spatial learning in the water maze. Eur J Neurosci 7:281–292
McEvoy et al. (2003)
Meek W, Chuch R, Wenk G, Olton D (1987) Nucleus basalis magnocellularis and medial septal area lesions differentially impair temporal memory. J Neurosci 7:3505–3511
Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 251:238–246
Messer WS Jr, Rajeswaran WG, Cao Y, Zhang HJ, el-Assadi AA, Dockery C, Liske J, O’Brien J, Williams FE, Huang XP, Wroblewski ME, Nagy PI, Peseckis SM (2000) Design and development of selective muscarinic agonists for the treatment of Alzheimer’s disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors. Pharm Acta Helv 74:135–140
Muir J, Dunnett S, Robbins T, Everitt B (1992) Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium, physostigmine, basal cortical lesions and intracortical grafts on a multiple choice serial reaction time task. Exp Brain Res 89:611–622
Nahas Z, George MS, Horner MD, Markowitz JS, Li X, Lorberbaum JP, Owens SD, McGurk S, DeVane L, Risch SC (2003) Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study. Neurocase 9:274–282
Nielsen J, Mena A, Williams I, Nocerini M, Liston D (1989) Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes. Eur J Pharmacol 173:53–64
Olincy A, Ross RG, Young DA, Roath M, Freedman R (1998) Improvement in smooth pursuit eye movements after cigarette smoking in schizophrenic patients. Neuropsychopharmacology 18:175–185
Page K, Everitt B, Robbins T, Marston H, Wilkinson L (1991) Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: diffrential dependence on cholinergic neuronal loss. Neuroscience 43:457–472
Perry KW, Nisenbaum LK, George CA, Shannon HE, Felder CC, Bymaster FP (2001) The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex. Biol Psychiatry 49:716–725
Polinsky RJ (1998) Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer’s disease. Clin Ther 20:634–647
Powchik P, Davidson M, Haroutunian V, Gabriel SM, Purohit DP, Perl DP, Harvey PD, Davis KL (1998) Postmortem studies in schizophrenia. Schizophr Bull 24:325–341
Raedler TJ, Knable MB, Jones DW, Urbina RA, Gorey JG, Lee KS, Egan MF, Coppola R, Weinberger DR (2003) In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. Am J Psychiatry 160:118–127
Reitstetter R, Lukas RJ, Gruener R (1999) Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure. J Pharmacol Exp Ther 289:656–660
Riley BP, Makoff AM, Mogudi-Carter M, Jenkins TJ, Williamson R, Collier DA, Murray RM (2000) High marker-density analyses of the α7-nicotine cholinergic receptor subunit (CHRNA7) gene region on chromosome 15q13-q14 and 5’ RACE cloning of fragments specific to CHRNA7 or its partial duplication. Schizophr Res 41:93
Robbins T, Everitt B, Marston H, Wilkinson J, Jones G, Page K (1989) Comparative effects of ibotenic acid and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes. Behav Brain Res 35:221–240
Rogers SL, Doody RS, Mohs RC, Friedhoff LT (1998a) Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Int Med 158:1021–1031
Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT (1998b) A 24-week, double blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease: Donepezil Study Group. Neurology 50:136–145
Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M (1999) Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 318:633–638
Rupniak N, Spencer T, Field M (1997) Enhanced performance of spatial and visual memory tasks by the selective acetylcholinesterase inhibitor E2020 in rhesus monkeys. Psychopharmacology 131:406–410
Samochocki M, Hoffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lubbert H, Albuquerque EX, Maelicke A (2003) Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 305:1024–1036
Santucci AC, Haroutunian V, Davis KL (1991) Pharmacological alleviation of combined cholinergic/noradrenergic lesion-induced memory deficits in rats. Clin Neuropharmacol 14:S1–8
Saykin A, Shtasel D, Gur R, Kester D, Mozley L, Stafiniak P et al. (1994) Neuropsycholoigcal deficits in neuroleptic naïve patients with first-episode schizophrenia. Arch Gen Psychiatry 51:124–131
Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 124:57–73
Schrattenholz A, Pereira EFR, Roth U, Weber KH, Albuquerque EX, Maelicke A (1996) Agonist responses of neuronal nicotinic are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49:1–6
Schwarz RD, Callahan MJ, Coughenour LL, Dickerson MR, Kinsora JJ, Lipinski WJ, Raby CA, Spencer CJ, Tecle H (1999) Milameline (CI-979/RU35926): a muscarinic receptor agonist with cognition-activating properties: biochemical and in vivo characterization. J Pharmacol Exp Ther 291:812–22
Shannon HE, Bymaster FP, Calligaro DO, Greenwood B, Mitch CH, Sawyer BD, Ward JS, Wong DT, Olesen PH, Sheardown MJ et al. (1994) Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther 269:271–281
Sitaram N, Weingarten H, Gillin J (1978) Human serial learning: enhancement with arecholine and choline and impairment with scopolamine. Science 201:274–276
Smith RC, Singh A, Infante M, Khandat A, Kloos A (2002) Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology 27:479–497
Stanhope KJ, Mirza NR, Bickerdike MJ, Bright JL, Harrington NR, Hesselink MB, Kennett GA, Lightowler S, Sheardown MJ, Syed R, Upton RL, Wadsworth G, Weiss SM, Wyatt A (2001) The muscarinic receptor agonist xanomeline has an antipsychotic-like profile in the rat. J Pharmacol Exp Ther 299:782–792
Stevens KE, Kem WR, Mahnir VM, Freedman R (1998) Selective alpha7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology 136:320–327
Stryjer R, Strous RD, Bar F, Werber E, Shaked G, Buhiri Y, Kotler M, Weizman A, Rabey JM (2003) Beneficial effect of donepezil augmentation for the management of comorbid schizophrenia and dementia. Clin Neuropharmacol 26:12–17
Tamlyn D, McKenna PJ, Mortimer A, Lund C, Hammond S, Beddeley A (1992) Memory impairment in schizophrenia: its extent, affiliations and neuropsychological character. Psychol Med 12:564–571
Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C (2000) A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group. Neurology 54:2269–2276
Tecle H, Schwarz RD, Barrett SD, Callahan MJ, Caprathe BW, Davis RE, Doyle P, Emmerling M, Lauffer DJ, Mirzadegan T, Moreland DW, Lipiniski W, Nelson C, Raby C, Spencer C, Spiegel K, Thomas AJ, Jaen JC (2000) CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology. Pharm Acta Helv 74:141–148
Thomsen T, Kaden B, Fischer JP, Bickel U, Barz H, Gusztony G, Cervos-Navarro J, Kewitz H (1991) Inhibition of acetylcholinesterase activity in human brain tissue and erythrocytes by galanthamine, physostigmine and tacrine. Eur J Clin Chem Clin Biochem 29:487–492
Wanibuchi F, Nishida T, Yamashita H, Hidaka K, Koshiya K, Tsukamoto S, Usuda S (1994) Characterization of a novel muscarinic receptor agonist, YM796: comparison with cholinesterase inhibitors in in vivo pharmacological studies. Eur J Pharmacol 265:151–158
Watanabe S, Nishikawa T, Takashima M, Toru M (1983) Increased muscarinic cholinergic receptors in prefrontal cortices of medicated schizophrenics. Life Sci 33:2187–2196
Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW (1994) Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 271:992–998
Wei J, Walton EA, Milici A, Buccafusco JJ (1994) m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC. J Neurochem 63:815–821
Wienrich M, Meier D, Ensinger HA, Gaida W, Raschig A, Walland A, Hammer R (2001) Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man. Life Sci 68:2593–2600
Winkler J, Suhr S, Gage F, Thal L, Fisher L (1995) Essential role of neocortical acetylcholine in spatial memory. Nature 375:484–487
Wood MD, Murkitt KL, Ho M, Watson JM, Brown F, Hunter AJ, Middlemiss DN (1999) Functional comparison of muscarinic partial agonists at muscarinic receptor subtypes hM1, hM2, hM3, hM4 and hM5 using microphysiometry. Br J Pharmacol 126:1620–1624
Woolf N, Butcher L (1989) Cholinergic systems: synopsis of anatomy and overview of physiology and pathology. In: The biological substrates of Alzheimer’s disease. Academic Press, New York, pp 73–86
Zarei M, Radcliffe KA, Chen D, Patrick JW, Dani JA (1999) Distribution of nicotinic acetylcholine receptor α7 and β2 submits on cultured hippocampal neurons. Neuroscience 88:755–764
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Friedman, J.I. Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacology 174, 45–53 (2004). https://doi.org/10.1007/s00213-004-1794-x
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DOI: https://doi.org/10.1007/s00213-004-1794-x